Skip Navigation


NDT Advance Access originally published online on March 14, 2008
Nephrology Dialysis Transplantation 2008 23(9):2804-2809; doi:10.1093/ndt/gfn118
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
23/9/2804    most recent
gfn118v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Calò, L. A.
Right arrow Articles by Pauletto, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Calò, L. A.
Right arrow Articles by Pauletto, P.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Absence of vascular remodelling in a high angiotensin-II state (Bartter's and Gitelman's syndromes): implications for angiotensin II signalling pathways

Lorenzo A. Calò1, Massimo Puato1, Silvia Schiavo1, Marco Zanardo1, Carmen Tirrito1, Elisa Pagnin1, Giulia Balbi1, Paul A. Davis2, Paolo Palatini1 and Paolo Pauletto1

1 Department of Clinical and Experimental Medicine, University of Padova, Italy 2 Department of Nutrition, University of California, Davis, CA, USA

Correspondence and offprint requests to: Lorenzo A. Calò, Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy. Tel: +39-049-8218701 and +39-049-8212279; Fax: +39-049-8754179; E-mail: renzcalo{at}unipd.it



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Methods
 Results
 Discussion
 References
 
Background. Angiotensin II (Ang II) is a powerful proinflammatory cytokine and growth factor that activates NF-{kappa}B, as well as NAD(P)H oxidase, and thus is a key factor for the induction and progression of cardiovascular diseases. Our previous studies have shown high Ang II and high blood pressure-driven proatherogenic remodelling in an animal model. To further explore Ang II in proatherogenic vascular remodelling independent of blood pressure, we used Bartter’s/Gitelman's syndrome (BS/GS) patients given their elevated plasma Ang II, yet normo/hypotension, because extensive mechanistic studies in these patients suggest they are a good model to explore Ang II-mediated signalling.

Methods. The study evaluated BS/GS patients for nitric oxide-dependent (FMD) and -independent vasodilation and intima-media thickness (IMT) of the carotid arteries compared with healthy subjects and essential hypertensive patients.

Results. The results showed the absence of IMT growth in BS/GS patients as cumulative mean-IMT and mean maximum-IMT levels in BS/GS did not differ from normotensives: 0.58 ± 0.09 mm versus 0.60 ± 0.09 and 0.67 ± 0.09 versus 0.70 ± 0.13 respectively, P = ns, but were significantly lower compared with hypertensive patients: 0.69 ± 0.13, P < 0.046 and 0.85 ± 0.19, P < 0.018, respectively. FMD was increased in BS/GS versus hypertensives or normotensive controls (10.8 ± 2.7% versus 6.5 ± 2.3 and 8.7 ± 1.9, P < 0.002 respectively) while endothelium-independent dilation did not differ (10.2 ± 3.6% versus 7.2 ± 1.9 and 8.2 ± 3.3, P = ns) between groups.

Conclusions. Our study in BS/GS provides to our knowledge the first clinical data that point to a direct proatherogenic role for Ang II. However, because the data are derived from findings in BS/GS and therefore are indirect, further studies in this and other models using more direct approaches should be pursued to demonstrate a direct proatherogenic effect of Ang II as well as further studies on Ang II type 2 receptor (AT2R) signalling that the spectrum of findings of this and other studies indicate as involved in the lack of vascular remodelling.

Keywords: angiotensin II; Gitelman's syndrome; intima–media thickness; NO dependent dilation; vascular remodeling



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Methods
 Results
 Discussion
 References
 
The proinflammatory effect of angiotensin II (Ang II), the major effector peptide of the renin–angiotensin–aldosterone system (RAAS), as key mechanism for the induction and progression of cardiovascular diseases, is drawing increasing scrutiny [1,2]. Disease development and progression in cardiomiopathy, nephropathy and, most notably, atherosclerosis is associated with increased expression and production of proinflammatory mediators such as IL-6, intercellular adhesion molecules (ICAM-1) and vascular cell adhesion molecules (VCAM-1) [2], chemotactic proteins (MCP-1) [2], nuclear transcription factor (NF-{kappa}B) [2] and growth factors [tumour necrosis factor alpha (TNF-{alpha}) and transforming growth factor beta (TGF-β)] [2]. Evidence for a critical role for both inflammation and Ang II in the progression and clinical sequelae of atherosclerosis is further strengthened by the demonstration that Ang II itself is a powerful proinflammatory cytokine and growth factor as it not only activates NF-{kappa}B, leading to the release of downstream inflammatory signalling molecules, but also activates NAD(P)H oxidase with induction of oxidative stress as well [3]; both are tightly linked with inflammation and atherosclerosis. Clinically, RAAS suppression with either Ang II type 1 receptor blockers (ARBs) or angiotensin converting enzyme inhibitors (ACEI) reduces common carotid artery intima–media thickness (IMT) [4,5] and might prevent or slow the development of atherosclerosis in addition to or independent of lowering blood pressure.

Previous studies from our laboratory [6,7] have shown that a proatherogenic remodelling of arteries occurs in an animal model of high Ang II and high blood pressure state. These studies, however, were unable to establish any clear-cut role for each factor. We have therefore turned to our cohort of patients with Bartter’s/Gitelman's syndrome (BS/GS) to evaluate Ang II effect(s) on vascular remodelling independent of its effect on blood pressure. BS/GS, caused by gene defects in specific kidney transporters and ion channels, presents a discordant clinical picture characterized by activation of RAAS, with increased plasma levels of Ang II and aldosterone, yet normo/hypotension reduced peripheral resistance and hyporesponsiveness to pressor agents [8]. Therefore, we have proffered these patients as a good system to explore the signalling pathways responsible for mediating the signalling of Ang II based on an extensive series of studies that have, in fact, provided mechanistic explanations for the vascular hyporeactivity typical of these patients and has led us to propose that BS/GS is a good human model to explore the mechanisms responsible for maintenance/controlling vascular tone and cardiovascular remodelling involved in the Ang II signalling [9–11].

In the present study we have evaluated in a group of BS/GS patients drawn from our cohort, both markers of functional and long-term structural remodelling such as nitric oxide (NO)-dependent and -independent vasodilation and IMT of the carotid arteries and compared these with those of essential hypertensive patients as well as normotensive controls.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Methods
 Results
 Discussion
 References
 
Patients
We recruited eight BS/GS patients (1 BS, 7 GS) (three males and five females, age range 24–54) with either BS (n = 1) or GS (n = 7) from our cohort of BS/GS patients; all have a full biochemical characterization with seven having undergone full genetic analysis and one awaiting the results of the genetic screenings (Tables 1 and 2).


View this table:
[in this window]
[in a new window]

  		Table 1 Clinical and laboratory data of BS/GS, hypertensive patients and healthy controls included in the study

 

View this table:
[in this window]
[in a new window]

  		Table 2 SLC12A3 mutations identified in the patients with Gitelman's syndrome

 
As control groups were used, 10 normotensive healthy subjects (6 males and 4 females, age 43.2 ± 10.6 years), from the staff of the Department of Clinical and Experimental Medicine, University of Padova, and 12 young untreated stage 1 essential hypertensive patients (6 males and 6 females, age 39.6 ± 11.2 years) selected from the cohort of patients of the Padova Hypertension Unit at the Department of Clinical and Experimental Medicine, Clinica Medica 4, included in the HARVEST Study (Hypertension and Ambulatory Recording Venetia Study), an observational study on the predictive value of 24-h ambulatory blood pressure for the development of sustained hypertension in young, 18–45 years old, never-treated patients with stage 1 hypertension [12,13].

The study protocol was approved by our institutional authorities and informed consent was obtained from all the study participants.

BS/GS patients have been taking only potassium supplements. Table 3 shows blood pressure values of all subjects included in the study.


View this table:
[in this window]
[in a new window]

  		Table 3 Functional and structural data of all the study's participants

 
All the subjects abstained from food, alcohol and caffeine-containing drinks for at least 12 h prior to the study. All subjects were reported to be consuming a normal Italian diet, which contains approximately 150 mmol of sodium/day.



   Methods
Top
 Abstract
 Introduction
 Patients and methods
 Methods
Results
 Discussion
 References
 
Carotid arteries IMT determination
Carotid ultrasound examinations were performed using the Aspen Advanced Ultrasound System (Acuson, USA) equipped with a linear probe (7–10 MHz). The procedure was carried out according to the Mannheim Intima-Media Thickness Consensus [14]. All subjects were examined in the same room in dim light, lying comfortably in a supine position. The right and left carotid arteries of each subject were examined by the same sonographer. Once an optimal longitudinal image was obtained, it was stored on 1/2-inch super VHS videotape. Images were analysed using a high-resolution videorecorder, coupled with a mouse-driven image analysis system. IMT, defined as the distance between the lumen-intima and the media–adventitia interfaces, was measured at end-diastole in the far wall of the right and left sides of the common carotid artery, the bulb and the internal carotid artery [15]. IMT measurements were expressed as cumulative mean of mean-IMT and maximum-IMT recorded in each vascular segment. To rule out potential interference of arterial enlargement with IMT measurements, the intraluminal diameter of common carotid artery 1 cm proximal to the dilatation of the bulb was measured at end diastole in lateral projection.

NO-dependent and -independent vasodilation
NO-dependent and -independent vasodilation was determined by a B-mode scan of the right brachial artery in longitudinal section above the elbow using a 7–10 MHz linear array transducer and a standard Aspen Advanced Ultrasound System (Acuson, USA) [16]. The transducer was held at the same point throughout the scan by a stereotactic clamp to ensure consistency of the image. A cuff was placed around the forearm just below the elbow. Measurements were obtained using an automatic system for computing the brachial artery diameter in real-time by analysing B-mode ultrasound images [17]. Endothelium-dependent response was assessed as dilation of the brachial artery to increased flow (flow-mediated dilation, FMD). After 1 min of acquisition for measuring basal diameter, the cuff was inflated for 5 min at 250 mmHg and then deflated to induce reactive hyperaemia. Endothelium-independent dilation was obtained by administration of a low dose (25 µg) of sublingual glyceril trinitrate (GTN). Ten minutes were allowed to recover baseline diameter after cuff deflation or GTN administration. FMD and response to GTN were calculated as the maximal percent increase in diameter above baseline. Arterial flow velocity was obtained by a pulsed Doppler signal at 70° to the vessel with the range gate (1.5 mm) in the centre of the artery. Flow velocity was measured at baseline and within 15 s after cuff release. Reactive hyperaemia was calculated as the maximum percent increase in flow after cuff release as compared to baseline flow. In our lab, reproducibility of FMD, measured in healthy volunteers on separate visits, is 8.4%.

Statistical analysis
Data were evaluated on a Power Macintosh G5 computer (Apple Computer, Cupertino, CA, USA) using the Statview II statistical package (BrainPower Inc., Calabasas CA, USA). Data are expressed as mean ± SD and analysed using Student's ‘t’-test and ANOVA for unpaired data. Values at a 5% level or less (P < 0.05) were considered significant.



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Methods
 Results
Discussion
 References
 
Cumulative mean-IMT levels in BS/GS did not differ from those of healthy controls: 0.58 ± 0.09 mm in BS/GS versus 0.60 ± 0.09, P = ns.

The mean maximum-IMT level in BS/GS also overlapped that of healthy controls 0.67 ± 0.09 versus 0.70 ± 0.13, P = ns. However mean-IMT and mean maximum-IMT levels in BS/GS were instead significantly lower compared to the values of mean-IMT and mean maximum-IMT found in hypertensive patients: 0.69 ± 0.13, P < 0.046 and 0.85 ± 0.19, P < 0.018, respectively (Table 3).

In agreement with previous studies in BS/GS [18,19], NO-dependent vasodilation showed an overactivity of the NO system. FMD was, in fact, increased in BS/GS patients compared to either hypertensive patients or normotensive healthy control subjects: 10.8 ± 2.7% versus 6.5 ± 2.3 and 8.7 ± 1.9 respectively, P < 0.001 (Table 3).

Endothelium-independent dilation did not differ between groups: 10.2 ± 3.6% in BS/GS versus 8.2 ± 3.3 in healthy subjects and versus 7.2 ± 1.9 in hypertensive patients, P = ns (Table 3).



   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Methods
 Results
 Discussion
References
 
Ang II is well recognized as playing a key role in vascular pathobiology, especially inflammation and remodelling [20–23]. However, it remains unclear whether these tissue effects are mediated by a direct effect of the hormone or indirectly through its influence on haemodynamics. That is, does Ang II have direct in vivo vascular effects independent of its effects on blood pressure? And do these vascular effects occur via independent pathways? It has been proven extremely difficult to separate those effects resulting from the action of Ang II on tissue from indirect effects resulting from Ang II influence on vascular tone regulation. This has made necessary the clarification of the biochemical mechanisms and pathways involved. Answering these questions will likely have a strong impact on the clinical ground, in particular on the suggested additive effects of ACE inhibitors and ARBs beyond their effect on blood pressure reduction. Despite considerable and ongoing efforts at defining the mechanisms and pathways of Ang II signalling [20–23], significant gaps still exist in our understanding of what mediates Ang II short- (vasoconstriction) and long-term (remodelling) signalling. The recent demonstration that chronic Ang II infusion, independently of any alterations in blood pressure, activates an important downstream transcription mechanism mediating vascular inflammation and remodelling [24], strengthens the case for a direct role of Ang II in cardiovascular remodelling.

The results of the current study on BS/GS documented the absence of IMT growth in BS/GS patients notwithstanding an elevated level of Ang II and RAAS activation. This is in contrast to the reports of elevated levels of Ang II causing IMT [4,5]. The absence of IMT growth in BS/GS is accompanied by both increased NO production, a known antiproliferative factor, and the absence in BS/GS of any increase in ERK1/2 phosphorylation, an established Ang II-mediated pathway which is linked to cardiovascular remodelling [25]. BS/GS patients likely represent a human model of endogenous Ang II type 1 receptor antagonism in which, despite the activation of RAAS and increased Ang II levels, these patients are protected from elevated Ang II's both short- and long-term signalling effects. The dissociation of blood pressure from Ang II effects is also found in BS/GS patients, which suggests that these patients might provide further insight into Ang II signalling. We have sought to advance BS/GS patients as representing the mirror image of hypertension and cardiovascular remodelling and therefore that BS/GS patients provide a unique clinical system that can be used to understand, clarify or confirm pathways linked to hypertension and cardiovascular remodelling based on studies in animal or cell culture models.

In the case of the current study, the contemporary absence of hypertension and vascular remodelling in BS/GS patients, however, could simply be the result of the fact that Ang II only causes vascular remodelling in the presence of hypertension. However, this then runs up against the growing body of evidence that points to the Ang II signalling pathways leading to vascular tone regulation and hypertension as being different from those leading to cardiovascular remodelling [20–23], thus directly mediating alterations of cardiovascular structure. The recent study by Zhan and co-workers [24] when joined with clinical studies demonstrating that either ARBs or ACE inhibitors reduce common carotid artery intima–media thickness [4,5], strongly point towards this direction. The results of our studies in BS/GS patients alongside those obtained in the present study also contribute to this possibility. In BS/GS, in fact, we have shown reduced susceptibility of LDL to oxidation [26] along with levels of CRP, acute phase reactants such as serum amyloid A (SAA), soluble VCAM and ICAM, and inflammatory process-related cytokines such as IL-6 and TNF-{alpha} that are all unchanged in BS/GS compared to normotensive healthy subjects [27]. At the cellular level, BS/GS patients have reduced expression of oxidative stress-related proteins such as p22phox and PAI-1 [28,29]. In addition, ERK 1/2 phosphorylation, an established Ang II-related response closely linked with cardiovascular remodelling, is unchanged, while I{kappa}B, the inhibitory subunit of NF-{kappa}B, was increased [25], pointing towards a reduced activity of NF-{kappa}B and reduced Ang II-induced-NF-{kappa}B-mediated transcription of genes involved in inflammation and remodelling. Moreover, BS/GS patients overexpress haeme-oxygenase-1 [28], which has known antioxidant and antiapoptotic effects [30]. These findings all together suggest that the cell redox state is unaltered as well as the long-term signalling pathway of Ang II, which determines cardiovascular remodelling and atherosclerosis as the induction of this later occurs via activation of the cell redox state [31]. Furthermore the downregulation of the RhoA/Rho-kinase pathway [11,29,32] and the up-regulation of the NO system [18,19] in BS/GS, when analysed alongside the absence of hypertension and of IMT growth in these patients documented in the current study, indirectly support the direct remodelling role of Ang II. In fact, since the Ang II long-term signalling, which also leads to cardiovascular remodelling besides the induction of hypertension, is downregulated in BS/GS, the lack of vascular remodelling in these patients could be viewed as indirect evidence that with the integrity of its long-term signalling Ang II would have been able to induce in these patients vascular remodelling independently from the presence of hypertension.

In addition, BS/GS as a unique human model of endogenous Ang II type 1 receptor (AT1R) antagonism may provide insight into Ang II signalling mediated by Ang II type 2 receptors (AT2R).

Most of the effects of Ang II are mediated via the AT1R while AT2R stimulation has, instead, been suggested to counteract many actions mediated by AT1R by inducing vasodilation, antiproliferation and apoptosis [33]. AT2R-related events may be implicated in improved remodelling of resistance arteries beyond blood pressure control seen in hypertensive as well as type 2 hypertensive diabetic patients upon selective AT1R antagonism which improved remodelling of resistance arteries beyond blood pressure control [4,34]. While the role of AT2R remains the object of active study, the results of current and previous studies on BS/GS vascular reactivity [9–11] suggest the involvement of AT2R signalling in these patients. Specifically, these patients show increased activation of the NO system [9,18,19] and reduced activity of the RhoA/Rho kinase system [11,29,31], both regulated through AT2R signalling [35,36]. Moreover, we have shown a markedly higher insulin sensitivity in BS/GS patients compared with healthy normotensive subjects [37], and the absence of microalbuminuria and endothelial dysfunction [37,38]. These are the opposite of those found in diabetes and hypertension that have been linked to Ang II signalling/insulin–glucose metabolism relationships. Finally, AT2R stimulation has been reported to downregulate ERK1/2 phosphorylation, which in turn results in reduced proliferation and apoptosis [39]. Again, the lack of increase in IMT, the increased NO system activation shown in our study along with the lack of increased ERK1/2 phosphorylation in our BS/GS patients [25] are all consistent with an involvement of AT2R-mediated signalling in BS/GS patients. The fact that blocking AT1R with ARBs reduces common carotid IMT in hypertensive patients [4] and might prevent or reduce the development of atherosclerosis independently from lowering blood pressure fits with this interpretation as blocking AT1R would make Ang II available for AT2R stimulation. This could be the case in BS/GS patients, a model of endogenous Ang II type 1 receptor antagonism in the presence of high Ang II but also in hypertensive patients where the treatment with losartan, an AT1R blocker, reduces carotid hypertrophy [4].

In conclusion, our study documenting IMT status in BS/GS patients provides, to our knowledge the first clinical data that point to a direct proatherogenic role for Ang II. However, because the data are derived from findings in BS/GS and therefore are indirect, further studies in this and other models using more direct approaches to demonstrate a direct proatherogenic effect of Ang II as well as further studies on AT2R signalling in humans should be pursued.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Methods
 Results
 Discussion
 References
 

  1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med (2005) 352:1685–1695.[Free Full Text]
  2. Pauletto P, Rattazzi M. Inflammation and hypertension: the search for a link. Nephrol Dial Transplant (2006) 21:850–853.[Free Full Text]
  3. Undurti N Das. Is angiotensin II an endogenous pro-inflammatory molecule? Med Sci Monit (2005) 11:155–162.
  4. Olsen MH, Wachtell K, Neland K, et al. Losartan but not atenolol reduce carotid artery hypertrophy in essential hypertension. A LIFE substudy. Blood Press (2005) 14:177–183.[CrossRef][Web of Science][Medline]
  5. Lonn E, Yusuf S, Dzavik V, et al. Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation (2001) 103:919–925.[Abstract/Free Full Text]
  6. Pauletto P, Chiavegato A, Giuriato L, et al. Hyperplastic growth of aortic smooth muscle cells in renovascular hypertensive rabbits is characterized by the expansion of an immature cell phenotype. Circ Res (1994) 74:774–788.[Abstract/Free Full Text]
  7. Pauletto P, Da Ros S, Capriani A, et al. Smooth muscle cell types at different aortic levels and in microvasculature of rabbits with renovascular hypertension. J Hypertens (1995) 13(Pt 2):1679–1685.[Web of Science][Medline]
  8. Naesens M, Steels P, Verberckmoes R, et al. Bartter's and Gitelman's syndromes: from gene to clinic. Nephron Physiol (2004) 96:65–78.[CrossRef]
  9. Calò LA. Vascular tone control in humans: the utility of studies in Bartter's/Gitelman's syndromes. Kidney Int (2006) 69:963–966.[CrossRef][Web of Science][Medline]
  10. Calò LA, Pessina AC, Semplicini A. Angiotensin II signaling in the Bartter's and Gitelman's syndromes, a negative human model of hypertension. High Blood Press Cardiovasc Prev (2005) 12:17–26.[CrossRef]
  11. Calò LA, Pessina AC. RhoA/Rho-kinase pathway: much more than just a modulation of vascular tone. Evidence from studies in humans. J Hypertens (2007) 25:259–264.[Web of Science][Medline]
  12. Palatini P, Graniero G, Mormino P, et al. Relation between physical training and ambulatory blood pressure in stage I hypertensive subjects. Results of the HARVEST trial. Circulation (1994) 90:2870–2876.[Abstract/Free Full Text]
  13. Sartori M, Semplicini A, Siffert W, et al. G-protein beta3-subunit gene 825T allele and hypertension: a longitudinal study in young grade I hypertensives. Hypertension (2003) 42:909–914.[Abstract/Free Full Text]
  14. Touboul PJ, Hennerici MG, Meairs S, et al. Mannheim intima-media thickness consensus on behalf of the advisory board of the third watching the risk symposium 2004, 13th European Stroke Conference, Mannheim, Germany, May 14, 2004. Cerebrovascular Diseases (2004) 18:346–349.[CrossRef][Web of Science][Medline]
  15. Pauletto P, Palatini P, Da Ros S, et al. Factors underlying the increase in carotid intima-media thickness in borderline hypertensives. Arterioscler Thromb Vasc Biol (1999) 19:1231–1237.[Abstract/Free Full Text]
  16. Deanfield J, Donald A, Ferri C. Endothelial function and dysfunction: Part I. Methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypertens (2005) 23:7–17.[CrossRef][Web of Science][Medline]
  17. Gemignani V, Faita F, Ghiadoni L, et al. A system for real-time measurement of the brachial artery diameter in B-mode ultrasound images. IEEE Trans Med Imaging (2007) 26:393–404.[CrossRef][Web of Science][Medline]
  18. Calo L, Davis PA, Milani M, et al. Increased endothelial nitric oxide synthase mRNA level in Bartter's and Gitelman's syndrome. Relationship to vascular reactivity. Clin Nephrol (1999) 51:12–17.[Web of Science][Medline]
  19. Calo L, D’Angelo A, Cantaro S, et al. Increased urinary NO2-/NO2- and cyclic GMP levels in patients with Bartter's syndrome: relationship to vascular reactivity. Am J Kidney Dis (1996) 27:874–879.
  20. Mehta PK, Griendling KK. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol (2007) 292:82–97.[CrossRef]
  21. Touyz RM. Role of angiotensin II in regulating vascular structural and functional changes in hypertension. Curr Hypertens Rep (2003) 5:155–164.[Web of Science][Medline]
  22. Ruiz Ortega M, Ruperez M, Esteban V, et al. Molecular mechanisms of angiotensin II-induced vascular injury. Curr Hypertens Rep (2003) 5:73–79.[Web of Science][Medline]
  23. Dzau VJ, Lopez-Ilasaca M. Searching for transcriptional regulators of Ang II-induced vascular pathology. J Clin Invest (2005) 115:2319–2322.[CrossRef][Web of Science][Medline]
  24. Zhan Y, Brown C, Maynard E, et al. Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling. J Clin Invest (2005) 115:2508–2516.[CrossRef][Web of Science][Medline]
  25. Calò LA, Davis PA, Pagnin E, et al. Linking inflammation and hypertension in humans: studies in Bartter's/Gitelman's syndromes. J Hum Hypertens (2007) 100:2309. Advance online publication: doi:10;.1038/sj.jhh.
  26. Calò L, Sartore G, Bassi A, et al. Reduced susceptibility of low density lipoprotein to oxidation in patients with overproduction of nitric oxide (Bartter's and Gitelman's syndrome). J Hypertens (1998) 16:1001–1008.[CrossRef][Web of Science][Medline]
  27. Davis PA, Mussap M, Pagnin E, et al. Early markers of inflammation in a high angiotensin II state. Results of studies in Bartter's/Gitelman's syndromes. Nephrol Dial Transpl (2006) 21:1697–1701.[Abstract/Free Full Text]
  28. Calò LA, Pagnin E, Davis PA, et al. Oxidative stress related factors in Bartter's and Gitelman's syndromes: relevance for Angiotensin II signalling. Nephrol Dial Transplant (2003) 18:1518–1525.[Abstract/Free Full Text]
  29. Pagnin E, Davis PA, Sartori M, et al. Rho kinase and PAI-1 in Bartter's/Gitelman's syndromes: relationship to angiotensin II signaling. J Hypertens (2004) 22:1963–1969.[CrossRef][Web of Science][Medline]
  30. Maines MD. The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol (1997) 37:517–554.[CrossRef][Web of Science][Medline]
  31. Dzau VJ. Tissue angiotensin and pathobiology of vascular disease. A unifying hypothesis. Hypertension (2001) 37:1047–1052.[Abstract/Free Full Text]
  32. Pagnin E, Semplicini A, Sartori M, et al. Reduced mRNA and protein content of Rho guanine nucleotide exchange factor (RhoGEF) in Bartter's and Gitelman's syndromes. Relevance for the pathophysiology of hypertension. Am J Hypertens (2005) 18:1200–1205.[CrossRef][Web of Science][Medline]
  33. Volpe M, Musumeci B, De Paolis P, et al. Angiotensin II AT2 receptor subtype: an uprising frontier in cardiovascular diseases? J Hypertens (2003) 21:1429–1443.[CrossRef][Web of Science][Medline]
  34. Schiffrin EL, Park JB, Intengam HD, et al. Correction of arterial structure and endothelial dysfunction in humans essential hypertension by the angiotensin receptor antagonist losartan. Circulation (2000) 101:1653–1659.[Abstract/Free Full Text]
  35. Savoia C, Tabet F, Yao G, et al. Negative regulation of Rho/Rho kinase by angiotensin II type 2 receptor in vascular smooth muscle cells: role in angiotensin II-induced vasodilation in stroke-prone spontaneously hypertensive rats. J Hypertens (2005) 23:1037–1045.[Web of Science][Medline]
  36. Kurisu S, Ozono R, Oshima T, et al. Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis. Hypertension (2003) 41:99–107.[Abstract/Free Full Text]
  37. Davis PA, Pagnin E, Semplicini A, et al. Insulin signaling, glucose metabolism and the angiotensin II signaling system. Studies in Bartter's/Gitelman's syndromes. Diabetes Care (2006) 29:469–471.[Free Full Text]
  38. Calò LA, Davis PA, Palatini P, et al. Urinary albumin excretion, endothelial dysfunction and cardiovascular risk: study in Bartter's/Gitelman's syndromes and relevance for hypertension. J Hum Hypertens (2007) 21:904–906.[CrossRef][Web of Science][Medline]
  39. Abadir PM, Periasamy A, Carey RM, et al. Angiotensin II type 2 receptor bradykinin B2 receptor functional heterodimerization. Hypertension (2006) 48:316–22.[Abstract/Free Full Text]
Received for publication: 4.12.07
Accepted in revised form: 11. 2.08


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
23/9/2804    most recent
gfn118v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Calò, L. A.
Right arrow Articles by Pauletto, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Calò, L. A.
Right arrow Articles by Pauletto, P.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?